Program Project on aging and Alzheimer's disease has been continuously funded since 1980, with Dr. Marilyn Albert as the PI. It was originally designed to study normal aging and Alzheimer's disease (AD), using neuropsychological and neuroimaging techniques. With the inception of the last funding period, the emphasis on Alzheimer's disease was expanded to include early detection in "questionable" patients; this now represents the primary focus of the research efforts. This Program Project was recently reviewed and we expect, on the basis of discussions with the funding agency, that it will be renewed. The specific aims of the Program Project are: (1) to recruit a large sample of subjects who meet criteria for "questionable" AD and a group of controls, (2) to evaluate the subjects at baseline with neuropsychological testing, neuroimaging procedures (i.e., Single Photon Emission Tomography [SPECT], Magnetic Resonance Imaging [MRI], and functional MRI [fMRI], and genetic testing (e.g., APOE-4 genotype), (3) to follow participants annually to determine which subjects develop AD over time, and (4) to examine the measures that predict progression of cognitive decline and the development of AD, both within and across the domains evaluated. Our research program is based on the Central Hypothesis that the development of AD follows a lengthy trajectory before full-blown symptoms are evident and that, in late-onset cases (patients who develop AD over the age of 65), disease is the result of multiple converging factors. Thus, it is likely that even very mildly impaired AD patients have substantial pathology in selected brain regions and therefore, by merging measurement of cognitive abilities and brain function related to these regions with an assessment of some of the factors that increase risk for disease, patients in the earliest stages of AD can be identified with considerable accuracy. This Central Hypothesis leads to several specific hypotheses with respect to the present Program Project: